Circadian Oscillation of Sulfiredoxin in the Mitochondria

Summary Hydrogen peroxide (H 2 O 2 ) released from mitochondria regulates various cell signaling pathways. Given that H 2 O 2 -eliminating enzymes such as peroxiredoxin III (PrxIII) are abundant in mitochondria, however, it has remained unknown how such release can occur. Active PrxIII-SH undergoes reversible inactivation via hyperoxidation to PrxIII-SO 2 , which is then reduced by sulfiredoxin. We now show that the amounts of PrxIII-SO 2 and sulfiredoxin undergo antiphasic circadian oscillation in the mitochondria of specific tissues of mice maintained under normal conditions. Cytosolic sulfiredoxin was found to be imported into the mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is promoted by H 2 O 2 released from mitochondria. The imported sulfiredoxin is degraded by Lon in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of sulfiredoxin provide the basis for sulfiredoxin oscillation and consequent PrxIII-SO 2 oscillation in mitochondria and likely result in an oscillatory H 2 O 2 release.